This application for an NIH RC1 Challenge Grant in Health and Science Research addresses the following Challenge Areas: (04) Clinical Research and (15) Translation Science. The specific Challenge Topics it addresses are 04-DK-104, Improve the diagnosis, staging and treatment of diseases of the liver;15-CA-111, Infectious Disease and Inflammation in Cancer, and 04-DK-111, Pilot and feasibility clinical research studies in diabetes, obesity, and metabolic, endocrine, digestive, liver, renal and urological diseases. Hepatitis B virus (HBV) is a major cause of serious liver diseases, including chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) throughout the world and the US, especially among minorities such as African Americans, Native Americans, and Asian Americans. HCC has a dismal prognosis unless detected early, but current screening methods have low sensitivity and specificity and are expensive. Recent clinical data have pointed to an association between HCC and HBV mutants with deletions in the preS2 region of the surface gene. We hypothesize that preS2 mutant HBV genomes play a causal role in HBV-associated carcinogenesis, and hence the appearance of these mutants in patients can be used as a marker for high risk of HCC. We will test this hypothesis, by confirming an association between preS2 mutants and advanced stages of hepatitis B with a cross-sectional study, and determining if the presence of these mutants can be used as a marker for increased risk of HCC development in patients with chronic hepatitis B in a case-control study. These studies, unlike previous ones, will be performed on samples from American patients. It is anticipated that these experiments will provide direct evidence on the possible utility of preS2 mutants as a marker of HCC risk in chronic hepatitis B, as well as lead in the future to the identification of molecular targets for the prevention and/or therapy of HCC. PUBLIC HEALTH RELEVANCE: Hepatitis B virus is a major cause of suffering and death in the world, by causing liver injury, cirrhosis (liver scarring) and, most importantly, liver cancer. Current treatment for liver cancer is inadequate, to a large extent because of our inability to detect the cancer early enough. We hope that our research can lead to the development of new ways for the early detection and hence treatment of liver cancer in these patients.